The goal of this proposal is to evaluate the potential of atiprimod, a drug previously explored for treating rheumatoid arthritis, to treat human multiple myeloma (MM) and other metastatic osteolytic bone diseases. Atiprimod is an orally bioavailable drug that originally completed phase I/lla clinical trials in rheumatoid arthritis patients, with patient exposure of up to one year without serious side effects and no observable toxicity. Recent data on atiprimod's ability to induce apoptosis and inhibit proliferation of multiple myeloma cell lines and to inhibit osteoclast-mediated bone resorption, along with an increase in our understanding of the growth factors that drive multiple myeloma make atiprimod a unique therapeutic opportunity, as the drug simultaneously affects the multiple key growth factors of this disease along with the possibility of also inhibiting bone destruction, a major sequela of multiple myeloma. Atiprimod therefore also may be useful in treating primary and metastatic bone cancer as it provides a new mechanism to inhibit osteoclast-driven bone resorption, a major debilitating effect of these cancers. The specific aims of this Phase I proposal involve the use of cell culture experiments and appropriate animal models to evaluate atiprimod's ability to inhibit MM proliferation. We will evaluate the mechanism-of-action of this drug using techniques to determine how it inhibits cell growth, promotes apoptosis and inhibits secretion of VEGF. Using an in vitro model of adhesion of MM to BMSC cells that enables us to study juxtracrine and paracrine production and biological significance of IL-6, VEGF, stromal cell-derived growth factor 1, and IGF-1 in the BM milieu mediating growth, survival, drug resistance, and migration of MM cells, we will focus on how atiprimod exhibits its anti-MM activity. Atiprimod will also be evaluated in two animal models of human multiple myeloma at Dana-Farber Cancer Institute. Successful accomplishment of these studies will lead to a Phase II proposal to evaluate atiprimod in human multiple myeloma patients. Because atiprimod has already been in human safety clinical studies and there is a wealth of clinical and preclinical studies already available on the drug, we would expect to be able to expediously file an IND for atiprimod to treat MM patients.